Neoplastic diseases, characterized by the proliferation of cells which are not subject to normal cell proliferating controls, are a major cause of death in humans and other mammals. Cancer chemotherapy has provided new and more effective drugs to treat these diseases and has also demonstrated that drugs which disrupt microtubule synthesis are effective in inhibiting the proliferation of neoplastic cells.
Microtubules play a key role in the regulation of cell architecture, metabolism and division. The microtubule systems of eukaryotic cells comprises a dynamic assembly and disassembly matrix in which heterodimers of tubulin polymerize to form microtubules in both normal and neoplastic cells. Within neoplastic cells, tubulin is polymerized into microtubules which form the mitotic spindle. The microtubules are then depolimerized when the mitotic spindle's use has been fulfilled. Agents which disrupt the polymerization or depolymerization of microtubules in neoplastic cells, thereby inhibiting the proliferation of these cells, comprise some of the most effective cancer chemotherapeutic agents in use.
Combretastatin A-4 (CA-4), isolated from the African bush willow, Combretum caffrum (Combretaceae) (Pettit, G. R., et al.; Experientia, 1989, 45, 209) shows exciting potential as an anticancer agent binding strongly to tubulin at a site shared with, or close to, the colchicine binding site (Lin, C. N., et al; Biochemistry, 1989, 28, 6984). The bond to tubulin prevents its polymerization into microtubules with anti-mitotic effect. CA-4 inhibits cell growth at as low as nanomolar concentrations and shares many structural features common to other tubulin-binding agents such as colchicine and podophyllotoxin.
The phosphate salt [CA-4P] (Pettit, G. R., et al.; Anticancer Drug Des., 1995, 10, 299), which has better water solubility than CA-4, has entered Phase II clinical trials.
It is the ability of combretastatins to damage tumor vasculature, thereby effectively starving tumors of nutrients, which makes them such exciting molecules.
Recently many studies have shown that a number of antiangiogenic agents, like CA-4P, can inhibit retinal neovascularization in a well-characterized murine model of ischemia-induced proliferative retinopathy.
These studies suggest that as CA-4P or new derivatives as other antiangiogenic agents, could be useful in the treatment of non-neoplastic diseases like ischemia-induced proliferative retinopathy (Griggs, J., et al., Am. J. Pathol., 2002, 160(3), 1097-103).
The spatial relationship between the two aromatic rings of combretastatin, colchicine and similar drugs is an important structural feature that determines their ability to bind to tubulin (McGown, A. T., et al., a) Bioorg. Med. Chem. Lett., 1988, 8(9), 1051-6; b) Bioorg. Med. Chem. Lett., 2001, 11(1), 51-4).
Since '80s researchers have discovered that the selective introduction of fluorine into biologically active molecules exerts an influence on activity. Therefore, important endeavour in drug design has been described and a number of compounds incorporating fluorine as a bioisosteric replacement for hydrogen were reported (Giannini, G., Current Medicinal Chemistry, 2002, 9, 687-712).